Intra articular drug delivery through an in-situ gelling system

Purpose: Our aim was to develop a biodegradable, in situ forming gel suitable for prolonged, i.e. several weeks, intra-articular drug delivery. Gel degradation kinetics, visualization, drug release and intra-articular biocompatibility were tested Methods: Gel synthesis PCLA-PEG-PCLA synthesis was performed by ring opening polymerization of L-lactide and ?-caprolactone in solution using PEG1500-diol as macroinitiator and tin(II) 2-ethylhexanoate as catalyst. To gain radiopacity, TIBO-capping of the PCLA-PEG-PCLA was perfomed using an excess of TIBO chloride. In-vitro gel behavior Phosphate buffer was added to the polymer (25wt %) and the resulting gel was kept at 37 -C for the duration of the experiment. At predetermined time points, residual gel weight was measured. In-vivo experiments Group 1 (n6 male Wistar rats); 100ml radiopaque gel was injected subcutaneous (n4) or in the knee joint (n2) and scanned regularly to visualize in vivo gel degradation longitudinally. Attenuation and volume of the gels were calculated. Group 2 (n10); 50 ml non-radiopaque gel was injected in the left knee, the right knee served as a control (50ml saline). mCT arthographies were acquired before injection, after 6 and 12 weeks to monitor cartilage quality (sGAG content is correlated inversely to Hexabrix influx) and quantity over time. After the last scan, knees were harvested for histology. Group 3 (n5); 500 ml of Celecoxib loaded gels (60 mg/g) were injected subcutaneously and blood samples were taken regularly to analyze drug release with UPLC. Results: In-vitro gel degradation Complete gel degradation tookw130- 140 days. Gel attenuation corresponded well with the measured polymer concentration over time, proving that mCT is indeed a good technique to quantify the amount of polymer present. In-vivo experiments Group 1: Total gel volume directly after subcutaneous injection by mCT was set at 100% and for all following time points the percentage of residual volume was calculated (figure 1). A controlled degradationwas observed for period of twelve weeks. Upon intra-articular injection, the gelwas contained within the knee while slowly degrading over a period of 4 weeks. Group 2: No changes in patellar cartilage quantity or quality occurred following intra-articular gel injection (p>0.10). At t0; t6weeks and t12weeks, cartilage volume L/R ratios were 1.02-0.12; 0.99-0.1; 1.08-.04 respectively; for attenuation 1.04-0.09; 1.05-0.08; 1.03-0.13. Histology confirmed that the gel did not affect the cartilage. Group 3; sustained drug release from the gel was confirmed with Celecoxib being detectable in plasma samples up to 40 days at a sustained level of w50-100 ìg/l (figure 2). Conclusions: Aliphatically-modified PCLA-PEG-PCLA form radiopaque and biocompatible gels which are able to deliver encapsulated drugs upon degradation over a period of several weeks. This system is therefore a promising candidate for intra articular drug delivery as a treatment for OA.